The immune system is one of the most sensitive targets for the toxicity of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant that continues to evoke public concern over safe exposure levels. During the current project period, the investigators demonstrated, for the first time, that suppression of a T cell-dependent immune response requires AhR expression in both CD4+ and CD8+ T cells. This finding represents a major breakthrough since no previous study has been able to provide a definitive link between suppression of T cell-dependent immune responses and direct effects of TCDD on T cells. The goals of this renewal application are to understand how AhR activation within T cells alters gene expression and to determine the functional consequences of these alterations. In this proposal, the investigators are capitalizing on the use of a well-characterized immune response known as an acute graft-versus-host response (GVHR). The main advantages of the GVHR model are two-fold: 'graft' T cells can be manipulated experimentally prior to transfer and their response can be tracked by flow cytometry after injection into the Fl host. By comparing T cells from AhR-/- and AhR+/+ mice, they can directly evaluate the consequences of TCDD-induced AhR activation in the T cells themselves. They hypothesize that both dioxin response element (DRE) - and non-DRE-mediated changes are induced in T cells by AhR activation and play important roles in their dysfunctional response. They hypothesize that AhR activation: (1) induces a death signal in T cells, (2) blocks the transduction of specific survival signals, and/or (3) alters the ability of the activated T cells to traffic to the site of antigen challenge. Current data support each of these possibilities. The studies proposed in this grant will track the antigen-induced response of CD4+ and CD8+ T cells in vivo over time as influenced by AhR activation. Tracking will occur on three levels: by expression of surface or cytoplasmic markers, by function, and by genomics. Taken together, the results of these studies will advance the fundamental understanding of how TCDD as an AhR ligand induces immune suppression. In addition, since activation of the AhR signaling pathway may induce a novel form of immune suppression, deducing this mechanism of action may provide new insights in basic immune regulation and may also reveal new possibilities for immunosuppressive therapies.